Processes for the preparation of S1P1 receptor modulators and crystalline forms thereof

Abstract

The present invention relates to salts, processes, and process intermediates useful in the preparation of (R)-2-(9-chloro -7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid of Formula (Ia), salts, and crystalline forms thereof. The compound (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid has been identified as an S1P1 receptor modulator that is useful in the treatment of S1P1 receptor-associated disorders, for example, diseases and disorders mediated by lymphocytes, transplant rejection, autoimmune diseases and disorders, inflammatory diseases and disorders (e.g., acute and chronic inflammatory conditions), cancer, and conditions characterized by an underlying defect in vascular integrity or that are associated with angiogenesis such as may be pathologic (e.g., as may occur in inflammation, tumor development, and atherosclerosis).

What is claimed is: 
     
       1. A salt that is (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid L-lysine salt. 
     
     
       2. A crystalline form of the salt according to  claim 1  having an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at about 6.9° and about 11.4°. 
     
     
       3. A crystalline form of the salt according to  claim 1  having an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at about 6.9°, about 11.4°, about 13.7°, about 21.7°, and about 22.9°. 
     
     
       4. A crystalline form of the salt according to  claim 1  having an X-ray powder diffraction pattern comprising peaks, in terms of 2θ, at about 6.9°, about 11.4°, about 13.6°, about 13.7°, about 19.8°, about 20.6°, about 21.7°, about 22.1°, and about 22.9°. 
     
     
       5. A crystalline form of the salt according to  claim 1  having an X-ray powder diffraction pattern substantially as shown in  FIG. 4 . 
     
     
       6. A crystalline form of the salt according to  claim 1  having a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 213° C. and about 217° C. 
     
     
       7. A crystalline form of the salt according to  claim 1  having a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 220° C. and about 224° C. 
     
     
       8. A crystalline form of the salt according to  claim 1  having a differential scanning calorimetry thermogram comprising an endotherm with a first extrapolated onset temperature between about 213° C. and about 217° C.; and a second extrapolated onset temperature between about 220° C. and about 224° C. 
     
     
       9. A crystalline form of the salt according to  claim 1  having a differential scanning calorimetry thermogram substantially as shown in  FIG. 5 . 
     
     
       10. A crystalline form of the salt according to  claim 1  having a thermogravimetric analysis profile showing less than about 0.1% weight loss up to about 110° C. 
     
     
       11. A crystalline form of the salt according to  claim 1  having a thermogravimetric analysis profile substantially as shown in  FIG. 5 . 
     
     
       12. A crystalline form of the salt according to  claim 1  having:
 1) an X-ray diffraction pattern comprising peaks, expressed in terms of 2θ, at about 6.9°, about 11.4°, about 13.7°, about 21.7°, and about 22.9°; 
 2) a differential scanning calorimetry thermogram comprising an endotherm with an extrapolated onset temperature between about 213° C. and about 217° C.; and/or 
 3) a thermogravimetric analysis profile showing less than about 0.1% weight loss up to about 110° C. 
 
     
     
       13. A crystalline form of the salt according to  claim 1  having:
 1) an X-ray diffraction pattern comprising peaks, expressed in terms of 2θ, at about 6.9°, about 11.4°, about 13.6°, about 13.7°, about 19.8°, about 20.6°, about 21.7°, about 22.1°, and about 22.9°; 
 2) a differential scanning calorimetry thermogram comprising an endotherm with a first extrapolated onset temperature between about 213° C. and about 217° C.; and a second extrapolated onset temperature between about 220° C. and about 224° C.; and/or 
 3) a thermogravimetric analysis profile showing less than about 0.1% weight loss up to about 110° C. 
 
     
     
       14. A salt that is an L-lysine salt of (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid, wherein the salt is prepared by a process comprising the steps of:
 a) hydrolyzing a compound of Formula (IIn): 
 
       
         
           
           
               
               
           
         
         wherein R 6  is C 1 -C 4  alkyl; 
         in the presence of a hydrolozing-step base and a hydrolyzing-step solvent to form said (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid; and 
         b) contacting said (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid with L-lysine or a salt thereof, in the presence of a contacting-step solvent and H 2 O to form said L-lysine salt of (R)-2-(9-chloro-7-(4-isopropoxy-3-(trifluoromethyl)benzyloxy)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl)acetic acid. 
       
     
     
       15. A composition comprising said salt according to  claim 1 . 
     
     
       16. The composition according to  claim 15 , wherein said salt or said crystalline form comprises about 97% or greater by weight of said composition. 
     
     
       17. A pharmaceutical composition comprising said salt according to  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
       18. A method for treating an S1P1 receptor-associated disorder selected from the group consisting of psoriasis, psoriatic arthritis, inflammatory bowel disease, rheumatoid arthritis, Crohn's disease, transplant rejection, multiple sclerosis, systemic lupus erythematosus, ulcerative colitis, type I diabetes, acne, myocardial ischemia-reperfusion injury, hypertensive nephropathy, glomerulosclerosis, gastritis, polymyositis, thyroiditis, vitiligo, hepatitis, and biliary cirrhosis in an individual comprising administering to said individual in need thereof a therapeutically effective amount of a salt according to  claim 1 . 
     
     
       19. A compound of Formula (IIm), or a salt thereof: 
       
         
           
           
               
               
           
         
         wherein R 6  is C 1 -C 4  alkyl. 
       
     
     
       20. The compound according to  claim 19 , wherein R 6  is CH 2 CH 3  or t-butyl. 
     
     
       21. A compound of Formula (IIn), or a salt thereof: 
       
         
           
           
               
               
           
         
         wherein R 6  is C 1 -C 4  alkyl. 
       
     
     
       22. The compound according to  claim 21 , wherein R 6  is CH 2 CH 3  or t-butyl. 
     
     
       23. The method according to  claim 18 , wherein said S1P1 receptor-associated disorder is biliary cirrhosis. 
     
     
       24. The method according to  claim 18 , wherein said S1P1 receptor-associated disorder is multiple sclerosis. 
     
     
       25. A method according to  claim 18 , wherein said S1P1 receptor-associated disorder disorder is psoriasis. 
     
     
       26. A method according to  claim 18 , wherein said S1P1 receptor-associated disorder disorder is rheumatoid arthritis. 
     
     
       27. A method according to  claim 18 , wherein said S1P1 receptor-associated disorder disorder is psoriatic arthritis. 
     
     
       28. A method according to  claim 18 , wherein said S1P1 receptor-associated disorder disorder is inflammatory bowel disease. 
     
     
       29. A method according to  claim 18 , wherein said S1P1 receptor-associated disorder disorder is Crohn's disease. 
     
     
       30. A method according to  claim 18 , wherein said S1P1 receptor-associated disorder disorder is ulcerative colitis.